Introduction: Impaired lower esophageal sphincter (LES) relaxation is the hallmark of achalasia and other spastic motor disorders of the esophagus. Too much LES relaxation (transient LES relaxation) leads to reflux disease. Therefore, it is quite clear that LES dysfunction contributes o significant medical morbidity and health related costs. Our current understanding is that the LES relaxation is neurogenic, mediated by vagus nerve which synapses with the inhibitory motor neurons located in the myenteric plexus of the esophagus. Hypothesis: Our hypothesis is that vagus nerve does not synapse with inhibitory motor neurons, rather it is the mechanical stretch caused by longitudinal muscle contraction of the esophagus that activates the inhibitory motor neurons located in the myenteric plexus through a stretch sensitive mechanism. These inhibitory motor neurons release nitric oxide and possibly other neurotransmitters in response to stretch and cause relaxation of the LES. Aim: The specific goals of our studies are: 1).To isolate neurons from the myenteric plexus of the rat esophagus and determine if they respond to mechanical stimulus, i.e., stretch, and release neurotransmitters such as nitric oxide and acetylcholine. Furthermore, we will determine the mechanism of stretch mediated activation of esophageal motor neurons. 2).To determine if vagus nerve branches synapse with the inhibitory motor neurons of the LES using anterograde neural tracer techniques. 3).To map the neural circuit in the myenteric plexus that mediates LES relaxation by multiphoton microscopy. Clinical Relationships: A large number of veterans suffer from the disorders of the esophagus. LES is a valve like mechanism between the esophagus and stomach. Motor disorders of the esophagus are related to poor relaxation of the LES and the fundamental abnormality in reflux disease is too much relaxation of the LES. Therefore, a better understanding of the mechanisms of LES relaxation is likely to lead to better treatment strategies in all forms of esophageal motor dysfunctions. Impact/Significance: We hope that an improved understanding of the mechanism of LES relaxation will results in better strategies to treat reflux disease and spastic motor disorders of the esophagus.